Estrogens and androgens are sex hormones that play essential roles in sex diferenciation, maturation, and reproductive functions of both men and women. Sex hormone levels increase significantly at puberty and maintain a relative constant level till the sudden drop at menopause for women and gradual decline for men after late 40s of age. There are many target organs of the two hormones beyond the sex organs. In women's health at and after menopause, effects of estrogens in uterus, breasts, vagina, CNS, bone, and cardiovascular system are mostly concerned. In men's health at and after andropause, effects of androgens in prostate, CNS, muscle, bone, and cardiovascular system are mainly concerned.
Hormone replacement therapy (HRT), used to refer to female hormone therapy for menopausal women, had been widely used for treatment of menopausal symptoms and prevention of aging related diseases till the unexpected benefit/risk results of Women's Health Initiative (WHI) trials were published (A. L. Hersh, et al. JAMA 291(1):47-53 (2004)). Although population of menopausal women and life expectancy continue to increase, the therapeutic options dealing with menopausal symptoms and aging related chronical diseases are limited due to the unclear cardiovascular outcomes of available therapies.
First generation therapeutic female hormones represented by Premarin have clinical benefits on CNS (reduction of hot flashes), bone (prevention of osteoporosis), breasts (prevention of breast cancer), and vagina (reduction in vaginal atrophy), clinical risk in uterus (increase cancer incidence), and complex benefit/risk effects on cardiovascular system (increase of blood clots and improvement of lipid profile). Progestin was combined with estrogens such as Prempro to counter the uterus effect of estrogens. Unfortunately, the synthetic progestin also counter the beneficial breasts effect of estrogens and add negative effects on cardiovascular system. Selective estrogen receptor modulators (SERMs) have mixed agonist/antagonist activities in different tissues and been developed to avoid the negative uterus effect of estrogens but loss the benefit in CNS. Since SERMs enhance the benefit effect of estrogens in the breasts, they are widely used to treat and prevent estrogen receptor(ER)-positive breast cancer. A combination therapy, Duavee™, of estrogens and SERM (bazedoxifene) was recently approved by US FDA for the treatment of menopausal symptoms and the prevention of postmenopausal osteoporosis. Bazedoxifene blocks the negative uterus effect of estrogens and estrogens compensate the CNS effect that SERMs do not have. ERs have complex relationship with cardiovascular system due to the indirect and multifactor effects. Cardiovascular outcome of a specific ER modulating compound depends on many factors including receptor selective profile, route of administration, lipid modulating profile, patient age, treatment history, and cardiovascular risk factors, which generates great challenge in new drug development to boost cardiovascular benefit/risk ratio.
Androgen therapy has been used to treat a variety of male disorders such as reproductive disorders and primary or secondary male hypogonadism. A number of natural or synthetic androgens have been investigated for the treatment of musculoskeletal disorders, such as bone disease, hematopoietic disorders, neuromuscular disease, rheumatological disease, wasting disease, and for hormone replacement therapy, such as female androgen deficiency. Testosterone (T) is available in several different forms including injection, patch, and gel for the treatment of hypogonadism. Testosterone therapy offers benefits on CNS (such as libido), muscle (improvement in BMI), and bone (prevention/treatment of osteoporosis), but is associated with increased risk in prostate (BPH, prostate cancer) and cardiovascular system (e.g. see B. Shehzad, et al. NEJM 363(2): 109-22 (2010)).
Selective androgen receptor modulators (SARMs) are designed to separate anabolic and androgenic activities of androgens. Androgenic activity of T in prostate and sebaceous glands is achieved by converting to biologically more active dihydrotestosterone (DHT) via tissue-selectively expressed enzymes, 5α-reductases. Inhibitors of 5α-reductases such as finasteride and dutasteride are used to block androgen effects in prostate and sebaceous glands. Combination of a 5α-reductase inhibitor and T supplement regimen can potentially offer T benefit in CNS with lower risk to develop BPH or prostate cancer in older patients (e.g. see A. Meehan. US 2009/0123571). SARMs are typically not substrates of 5-alpha-reductase and have good selectivity towards muscle, bone, and CNS over prostate and sebaceous glands based on the non-reductable mechanism alone. However, SARMs are not designed to mitigate negative cardiovascular effects of androgens, which results in concerns of developing SARMs for long-term use despite of their demonstrated benefits on muscle, bone, and CNS.
Humans need both estrogens and androgens with different ratios in males and females. Endogenous estrogens and androgens are generated in the same biosynthetic pathways and their levels are tightly controlled by the gonadal feed-back mechanism. Androgens have a negative feed-back mechanism and biosynthesis of androgens decrease when their circulation level increases. It has been noticed that endogenous androgen level and androgen supplements have different effects on cardiovascular systems. It has been hypothesized that negative cardiovascular outcome of androgens is negatively correlated with endogenous androgen production and thus the negative impact of exogenous androgens on cardiovascular system may be related to block endogenous androgen production through the feed-back mechanism (e.g. see L. Zhi. WO 2013/134311). Estrogens have a dual feed-back mechanism where negative feed-back mechanism works at lower levels and positive feed-back mechanism dominates at high levels. As a result, the effect of exogenous estrogens on cardiovascular system is more complicated than that of androgens. Therapeutic intervention of the gonadal feed-back system can manipulate endogenous hormone production. Gonadotropin-releasing hormone receptor antagonists and agonists are clinically used to shut down endogenous sex hormone production as referred to as “chemical castration”. Some SERM compounds have demonstrated activity to increase luteinizing hormone (LH) secretion in men, which leads to increase in endogenous T production (e.g. see V. Birzniece, et al. JCEM 95(12): 5443-8 (2010)). Enclomiphene is currently developed as a potential oral “T therapy” for hypogonadism (R. Wiehle, et al. BJUI 112: 1188-200 (2013)).
Steroid hormone binding globulin (SHBG) is a glycoprotein that binds to androgens and estrogens in circulation and, as a result, reduces the hormone levels that are available for binding to their target hormone receptors. SHBG is produced in the liver and affected by the hormone levels in the liver. Estrogen supplements and SERMs generally increase the production of SHBG, especially when they are administrated via oral route. Androgen supplements and SARMs tend to decrease SHBG production. Since SHBG level affects biologically available sex hormone levels, biological activity of the hormones can be affected by the effects of supplemental hormones on SHBG.
Estrogens are biosynthesized from androgens by aromatase. T therapy may provide additional benefit of estrogens through the aromatase conversion (e.g. see J. S. Finkelstein, et al. NEJM 369: 1011-22 (2013)). Estrogen therapies lacking androgen component and SARMs lacking estrogen component may not be a complete hormone profile replacement.
Hormone therapies that can address all of the major concerns of risk factors are in a great need for rapidly growing aging population. It is among the objects herein to provide such methods and compositions that combine existing therapeutic classes to address the broader safety issues of the currently available therapies.